MECHANISMS IN ENDOCRINOLOGY: The pathophysiology of transient congenital hypothyroidism

Abstract

Transient congenital hypothyroidism (TCH) refers to congenital hypothyroidism which spontaneously resolves in the first few months or years of life. Currently, there is a paucity of reliable markers predicting TCH at diagnosis, and the diagnosis is established following the withdrawal of levothyroxine therapy around 3 years of age. The incidence of TCH is increasing, and it is a major contributor to the overall increase in the incidence of CH in recent studies. Both genetic factors, in particular mutations affecting DUOX2 and DUOXA2, and environmental factors, for example, iodine deficiency and excess, anti- TSHR antibodies and exposure to antithyroid or iodine-rich medications, may cause TCH. Resolution of TCH in childhood may reflect both normal thyroid physiology (decreased thyroid hormone biosynthesis requirements after the neonatal period) and clearance or cessation of environmental precipitants. The relative contributions and interactions of genetic and environmental factors to TCH, and the extent to which TCH may be prevented, require evaluation in future population-based studies.

Figure 1

Association between the efficiency of thyroid hormone biosynthesis and transient CH. Created with BioRender.com.

Figure 2

Summary of causes of transient CH which may involve maternal environment during gestation, nutritional composition and passage of medication in breast milk, and neonatal exposure to unfavourable iodine status, contributory medication, and the presence of specific genetic mutations or haemangioma. Artefactual causes are shown in italics. Created with BioRender.com.

Figure 3

Schematic illustrating the key molecules required for thyroid hormone biosynthesis. Mutations in any of these molecules (TSHR, NIS, Pendrin, TG, TPO, DUOX2, DUOXA2, IYD) may cause CH and mutations in the NADPH-oxidase DUOX2 and its accessory protein DUOXA2 are particularly implicated in transient CH. Created with BioRender.com.

Figure 4

Schematic demonstrating TSH assay interference by heterophile antibodies (targeting assay reagents) and macro-TSH, which refers to the presence of circulating, bioinactive TSH held in complex by immunoglobulins. Although bioinactive, macro-TSH is immunoreactive and may be detected by laboratory immunoassays, resulting in spuriously high readings. Both types of antibody may affect fetal TSH results by transplacental passage. Created with BioRender.com.